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The rise and fall of the clot buster

Streptokinase, the first thrombolytic drug to reach the market, achieved fame as the iconic clot buster.

Source: Sebastian Kaulitzki / Dreamstime.com

Streptokinase was discovered after it was observed that haemolytic Streptococcus bacteria from patients with an acute febrile illness agglutinated in the presence of plasma, but not serum

When streptokinase was discovered in the 1930s, it first became known as fibrinolysin because it helps to break down fibrin, the main component of blood clots. It was renamed in 1945 but took a further three decades to be approved for the treatment of venous thromboembolism. In the mid-80s it was approved to treat acute myocardial infarction (AMI), earning it the ‘clot buster’ epithet.

Peter Sleight, cardiovascular researcher at the University of Oxford, UK, was a medical student in 1947 and recalls that the only treatment for AMI at the time was bed rest, leading to hospital mortality of about 20%.

“In the years that followed, beta-blockers and aspirin plus streptokinase became part of the package of care,” says Sleight, who chaired the ISIS collaborative group whose pioneering multinational trials helped to change clinical practice for heart attack patients. “Aspirin reduced mortality by 25% and then streptokinase, if given within the first few hours of onset, reduced it by another 25%.”

Early days

It was US bacteriologist William Tillett who discovered streptokinase after he observed that haemolytic Streptococcus bacteria from patients with an acute febrile illness agglutinated in the presence of plasma, but not serum. The most likely candidate for this agglutination was fibrinogen, which is present in plasma but missing from serum. Tillett reasoned that if he mixed plasma and streptococci together, the fibrinogen would adhere to the bacteria and so would not be available for blood clotting.

When Tillett first compared the clotting power of plasma with and without streptococci, he found no difference, so he assumed his theory was wrong. But a second look some time later showed that the plasma exposed to the bacteria had subsequently liquefied. Further experiments, reported in 1933, confirmed that Streptococcus haemolyticus isolated from infected patients produced a fibrinolytic agent, which he called fibrinolysin.

In 1941, it was shown by Tillett’s colleague Jacob Haskell Milstone that streptococcal fibrinolysin requires a plasma protein co-factor to dissolve fibrin, and this became known as plasminogen. In 1944, L. Royal Christensen and Melvin Kaplan independently confirmed that fibrinolysin converts plasminogen to plasmin, which in turn breaks down fibrin blood clots. Christensen renamed fibrinolysin “streptokinase” in 1945.

Promising results

Streptokinase was first used in the clinic in 1947 to treat haemothorax, in which blood builds up in the space between the lungs and the chest cavity. There was great interest in the potential of streptokinase to treat coronary thrombosis, but the initial samples were only 10% pure — they were a mixture of streptokinase, deoxyribonuclease, hyaluronidase and other streptococcal enzymes — and caused febrile reactions when used intravenously or injected into closed spaces.

Streptokinase was a huge advance when there was nothing else and, when combined with aspirin, it halved mortality in what was at that time a lethal disease.

In the 1950s, Lederle Laboratories (now part of Pfizer) developed a purified preparation of streptokinase. A pilot study reported in 1958 that AMI patients could tolerate a 30-hour infusion of streptokinase and that mortality was lowest in those treated within the first 14 hours of developing symptoms. Those treated 20–72 hours after the first symptoms had a similar mortality to untreated patients. Further results published the following year confirmed the promising results and showed that high levels of plasma thrombolytic activity did not harm infarcted tissue, including the myocardium.

Growing interest in two other thrombolytic agents, urokinase and tissue plasminogen activator (tPA), temporarily put streptokinase on the back burner, especially as Lederle was experiencing quality control issues with its formulation. But in the 1960s, Behringwerke in Germany and Kabi Pharmacia (now part of Pfizer) in Sweden developed a more reliable formulation and streptokinase was the centre of attention once again. It was shown to be effective in treating venous thromboembolism and was licensed for intravenous use, including treating deep vein thrombosis and pulmonary embolism.

Reduced mortality

Several studies suggested that streptokinase could be used to treat AMI, but many clinicians remained unconvinced. “Some small trials were positive, others negative, so it was difficult to draw conclusions,” recalls Sleight.

In 1985, Salim Yusuf, a research student in Sleight’s laboratory in Oxford, carried out a meta-analysis of 33 randomised controlled trials of fibrinolytic therapy (mainly streptokinase). The results revealed a highly significant 22% reduction in deaths and an even larger reduction in reinfarction.

Two large studies were then set up to investigate conclusively the role of streptokinase in treating AMI. An Italian collaboration known as GISSI tested the addition of intravenous streptokinase to standard therapy[1], and a second international study (ISIS-2) tested the effects of streptokinase, aspirin and a combination of the two drugs[2].

Sleight remembers how the studies came about. “Richard Peto, Rory Collins and I planned ISIS-2 around my dining table. We then went to Germany to ask Behringwerke for financial support. None of us can remember whose idea it was to include aspirin, and Behringwerke were very unkeen because of the bleeding risk, but in the end they agreed,” he says. “Both aspirin and streptokinase were off patent, so we were fortunate to get the £2 million we needed for what was, at that time, the largest ever study of MI treatment.”

It was fortunate that Behringwerke agreed to the inclusion of aspirin. In ISIS-2, which included more than 17,000 AMI patients treated within 24 hours of symptom onset, vascular mortality after 5 weeks was 25% lower with streptokinase alone than with a placebo, and 23% lower with just aspirin[2]. But combining the two drugs almost doubled the benefit, leading to a reduction in mortality of 42%.

In GISSI, which included nearly 12,000 AMI patients, mortality after 21 days was 18% lower with streptokinase than with controls receiving standard treatment[1]. As with the earlier streptokinase studies, those patients treated most promptly after symptom onset benefited the most.

Clot buster rivalry

But while streptokinase was proving its worth, tPA was once again being taken seriously. It was cloned in 1982, opening the way to large-scale studies of its thrombolytic effects and raising comparisons with streptokinase. For example, the TIMI-1 (thrombolysis in myocardial infarction 1) trial showed that tPA had greater benefits on arterial reperfusion, patency and 48-week mortality than streptokinase[3],[4]. And the GUSTO (global utilisation of streptokinase and tissue plasminogen activator for occluded coronary arteries) study showed that tPA had a lower mortality rate than streptokinase after both 30 days and 12 months[6].

However, two other studies raised questions over the superiority of tPA. The GISSI-2 study failed to show any survival advantage of tPA after 6 months[7], and ISIS-3 — the largest comparative study of clot buster therapies with more than 40,000 AMI patients — not only failed to show a survival advantage after 35 days for tPA, but showed an excess of strokes in patients treated with the drug[8]. Overall mortality was similar for streptokinase and tPA, although the reinfarction rate was lower with tPA (2.93% versus 3.47%). Strokes occurred in 1.39% and 1.04% of tPA and streptokinase patients, respectively.

“Despite GISSI-2 and ISIS-3, tPA still won out, especially in the United States, because it was easier to use than streptokinase as it could be given as a bolus rather than an infusion,” says Sleight. “In the UK, we were cost conscious and used streptokinase because it was a lot cheaper than tPA.”

A busted flush?

The clot buster rivalry of the 1990s came to an abrupt end when studies showed that primary percutaneous coronary intervention (PCI) yielded better results than any of the pharmacological options. In 2000, the PRAGUE (primary angioplasty in patients transferred from general community hospitals to specialised PTCA units with or without emergency thrombolysis) study showed that the primary endpoint (rate of death, reinfarction or stroke rate at 30 days) was significantly lower after prompt primary angioplasty than thrombolysis[9].

Supportive data from PRAGUE 2[10] and a meta-analysis of 23 randomised comparative trials[11] resulted in a rapid change in AMI management in the UK. By the middle of 2011, 94% of ST-segment-elevation myocardial infarction (STEMI) patients in England who received reperfusion treatment were treated by primary PCI, compared with just 46% in the latter part of 2008.

In 2013, the National Institute for Health and Care Excellence issued guidance on the acute management of STEMI. It concluded that STEMI patients should be offered coronary angiography, with follow-on primary PCI if indicated, if they present within 12 hours of symptom onset and primary PCI can be delivered within 120 minutes of the time when fibrinolysis could have been given. Clot buster treatment with streptokinase or tPA should be reserved for those to whom primary PCI cannot be delivered in this timeframe.

However, tPA has been given a new lease of life thanks to its fibrinolytic effects on ischaemic stroke; NICE recommends that it should be started not more than 4.5 hours after the onset of stroke symptoms. But streptokinase does not have this indication.

A global role

“Streptokinase was a huge advance when there was nothing else and, when combined with aspirin, it halved mortality in what was at that time a lethal disease,” says Sleight. Despite its now minimal presence in AMI treatment in the UK and the United States, streptokinase continues to play a major role at a global level. It is used as thrombolysis for acute MI in about half of countries worldwide because it is affordable, explains Sleight, adding: “In countries where patients do not have rapid access to catheterisation, streptokinase is still important.”